Around 150 BC, Mesopotamia was under the control of the Parthian Empire. Mesopotamia became a battleground between the Romans and Parthians, with western parts of Mesopotamia coming under ephemeral Roman control. In AD 226, the eastern regions of Mesopotamia fell to the Sassanid Persians. The division of Mesopotamia between Roman (Byzantine from AD 395) and Sassanid Empires lasted until the 7th century Muslim conquest of Persia of the Sasanian Empire and Muslim conquest of the Levant from Byzantines. A number of primarily neo-Assyrian and Christian native Mesopotamian states existed between the 1st century BC and 3rd century AD, including Adiabene, Osroene, and Hatra.

Mesopotamia is the site of the earliest developments of the Neolithic Revolution from around 10,000 BC. It has been identified as having "inspired some of the most important developments in human history including the invention of the wheel, the planting of the first cereal crops and the development of cursive script, mathematics, astronomy and agriculture".

The regional toponym Mesopotamia (/ˌmɛsəpəˈteɪmiə/, Ancient Greek: Μεσοποταμία " between rivers"; Arabic: بلاد الرافدين، بین النهرین‎ bilād ar-rāfidayn; Kurdish: میزۆپۆتامیا‎; Persian: میان‌رودان‎ miyān rudān; Syriac: ܒܝܬ ܢܗܪܝܢ‎ Beth Nahrain "land of rivers") comes from the ancient Greek root words μέσος (meso) "middle" and ποταμός (potamos) "river" and translates to "(Land) between two/the rivers". It is used throughout the Greek Septuagint (ca. 250 BC) to translate the Hebrew and Aramaic equivalent Naharaim. An even earlier Greek usage of the name Mesopotamia is evident from The Anabasis of Alexander, which was written in the late 2nd century AD, but specifically refers to sources from the time of Alexander the Great. In the Anabasis, Mesopotamia was used to designate the land east of the Euphrates in north Syria.

The Aramaic term biritum/birit narim corresponded to a similar geographical concept. Later, the term Mesopotamia was more generally applied to all the lands between the Euphrates and the Tigris, thereby incorporating not only parts of Syria but also almost all of Iraq and southeastern Turkey. The neighbouring steppes to the west of the Euphrates and the western part of the Zagros Mountains are also often included under the wider term Mesopotamia.